Pulmonary aerosol delivery device and method

ABSTRACT

A device and method for delivering an aerosolized liquid having therapeutic properties to a user&#39;s lungs. The compact and convenient device includes a housing of such size that it can be held in a user&#39;s one hand with an exit opening in the housing for directing the aerosol to the user&#39;s mouth. The housing encloses a dispensing system for containing the liquid to be aerosolized and delivering it to an electrohydrodynamic apparatus and an electrohydrodynamic apparatus for aerosolizing the liquid and delivering the aerosol to the exit opening. The electrohydrodynamic apparatus produces a cloud of aerosolized liquid droplets having a monodispersed respirable droplet size and near zero velocity. The aerosolizing apparatus includes a plurality of spray sites each having a tip end, the spray sites cooperating with a charge source to result in an aerosolized spray from at least one tip end, a plurality of discharge electrodes downstream of the tip ends, and a plurality of reference electrodes downstream of the plurality of discharge electrodes.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation of copending U.S. application Ser. No.10/161/545, filed Jun. 3, 2002, which is a continuation of U.S.application Ser. No. 09/469,042, filed Dec. 21, 1999, now U.S. Pat. No.6,397,838 B1, which is a continuation-in-part of U.S. application Ser.No. 09/220,249, filed Dec. 23, 1998, now abandoned, each of which isfully incorporated herein by reference.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

Not applicable

REFERENCE TO MICROFICHE APPENDIX

Not applicable

FIELD OF THE INVENTION

This invention relates to devices and methods for delivering anaerosolized liquid to a user's lungs, and particularly an aerosolizedliquid having therapeutic properties.

BACKGROUND OF THE INVENTION

For some therapeutic agents, delivery of the aerosolized liquid withouta propellant is preferred. Such liquids may be aerosolized, for example,by an electrohydrodynamic apparatus. The liquid to be aerosolized ismade to flow over a region of high electric field strength, whichimparts a net electric charge to the liquid. This electric charge tendsto remain on the surface of the liquid such that, as the liquid exitsthe nozzle, the repelling force of the surface charge balances againstthe surface tension of the liquid, forming a cone (a “Taylor cone” asdescribed in, e.g., M. Cloupeau and B. Prunet-Foch, “ElectrohydrodynamicSpraying Functioning Modes: A Critical Review,” J. Aerosol Sci., Vol.25, No. 6, pp. 1021, 1025-1026 (1994)). In the region of the tip of thecone, which has the greatest charge concentration, the electrical forceexerted on the liquid surface overcomes the surface tension, generatinga thin jet of liquid. The jet breaks into droplets of more or lessuniform size, which collectively form a cloud that may be inhaled by auser to deliver the aerosol to the user's lungs.

Dr. Ronald Coffee of Oxford University, Oxford, England, has proposedand developed methods of aerosolizing pharmaceutical formulations anddischarging the aerosol particles prior to their delivery to a user. Onesuch method uses an electrohydrodynamic apparatus having a single spraysite (nozzle) surrounded by four discharge electrodes and a groundedshield to produce a monodispersed spectrum of particle sizes.

Known pulmonary delivery devices that use electrohydrodynamic sprayingare unwieldy and require connection to either an alternating currentpower supply or a large direct current power supply. These conventionaldevices are suitable for use in hospital or other clinical applications,such as for administering a therapeutic agent during a scheduledtreatment appointment, but generally are not suitable for use directlyby a user on a demand or as-needed basis outside a clinical setting.Conventional devices are particularly unsuited for use during a user'sregular activities at home, at work, while traveling, and duringrecreational and leisure activities.

Known pulmonary delivery devices that use electrohydrodynamic sprayingalso lack a sufficient volumetric flow rate to deliver a desired amountof certain therapeutic liquids during the inhalation of one to twobreaths by a user. Attempts to increase the flow rate generally haveresulted in even more bulky devices unsuitable for hand-held use. Thesedelivery devices also are not generally capable of spraying liquidshaving a broad range of conductivities.

It is an object of the invention to provide a device and method thatconveniently delivers an aerosolized liquid to a user's lungs. It isanother object of the invention to provide a compact, portable,hand-held pulmonary delivery device that may be used in a variety ofindoor and outdoor locations. The device would allow users to administertherapeutic agents on an as-needed basis in nonclinical settings andprovide advantages over conventional devices used by hospitals andclinicians.

It is a further object of the invention to provide a compact andconvenient device and method that delivers an increased volumetric flowrate of liquid so that a desired amount of a therapeutic liquiddispersed into respirable particles may be administered during theinhalation of one to two breaths by a user.

It is another object of the invention to provide a device and methodcapable of electrohydrodynamic spraying of therapeutic liquids having abroad conductivity range in a compact and convenient device.

It is yet another object of the invention to provide an apparatus foraerosolizing liquid that is useful in the delivery to a user, in theform of respirable particles, of a desired amount of a therapeuticliquid within a broad conductivity range.

SUMMARY OF THE INVENTION

The invention described here provides a compact, convenient device andmethod for delivering an aerosolized liquid having therapeuticproperties to a user's lungs by electrohydrodynamic spraying.Preferably, the device is small enough that it can be comfortablycarried by a user, for example, in shirt pocket or purse, and has aself-contained power supply so that it can be used anywhere. The devicemay be disposable or reusable.

In a preferred embodiment, the pulmonary aerosol delivery devicecomprises a housing sized so that it can be held in a user's hand andhaving an exit opening for directing the aerosol to the user's mouth.The housing encloses a dispensing system for containing the liquid to beaerosolized and delivering it to an electrohydrodynamic apparatus, anelectrohydrodynamic apparatus for aerosolizing the liquid and deliveringthe aerosol to the exit opening; and a power supply system for providingsufficient voltage to the electrohydrodynamic apparatus to aerosolizethe liquid. The power supply system may comprise a battery and a DC toDC high voltage converter so the device may be cordless.

The liquid to be aerosolized may comprise a drug. The dispensing systemof the device may include a containment vessel for containing the drug,which may be a holder for a drug enclosed in single dose units, aplurality of sealed chambers each holding a single dose of a drug, or avial for enclosing a bulk supply of a drug. The containment vessel mayhave antimicrobial properties and may be capable of maintaining thesterility of a sterile drug placed therein.

The dispensing system delivers a single dose of the drug from thecontainment vessel to the electrohydrodynamic apparatus, which may beaccomplished using a metering system. The metering system may include achamber for collecting a predetermined volume of liquid having an inletcommunicating with the containment vessel and an outlet communicatingwith the electrohydrodynamic apparatus; a chamber housing above thechamber; a chamber housing spring adjacent to the chamber; and a buttonspring above the chamber housing. The button spring exerts a downwardforce against the chamber housing when an actuator button is depressedto force liquid in the chamber through the outlet and the chamberhousing spring exerts an upward force against the chamber housing whenthe actuator button is released. The upward travel of the chamberhousing induces a vacuum in the chamber to draw liquid from thecontainment vessel through the inlet. The chamber volume is controlledby an adjustable stop that limits the upward travel of the chamberhousing. The metering system may further include check valves at thechamber inlet and outlet to provide unidirectional liquid flow.

The device may further include a control circuit communicating with thedispensing system, the electrohydrodynamic apparatus and the powersupply system. The control circuit may include an on/off powerindicator, a power save feature, or a lockout to prevent use by anunauthorized user.

The control circuit may include an actuation device for initiating theflow of aerosolized liquid. The actuation device may be a breath sensorfor detecting a user's inhalation of one or more breaths, such as aflapper switch, a pressure transducer, an air motion detector, or an airvelocity detector, which cooperates with the electrohydrodynamicapparatus to initiate the flow of aerosolized liquid. The actuationdevice also may be a manual actuator on the exterior of the housing.

The electrohydrodynamic apparatus of the device may be capable ofaerosolizing the liquid at a flow rate of at least about 20 μL/sec. Italso may be capable of aerosolizing the liquid into droplets such thatat least about 80% of the droplets have a diameter of less than or equalto about 5 microns.

The housing of the device may have antimicrobial properties. The exitopening of the housing may be movable to assist in directing the aerosolto the user's mouth.

In another preferred embodiment, a pulmonary aerosol delivery deviceincludes a housing sized so it can be held in a user's hand and havingan exit opening for directing the aerosol to the user's mouth. Thehousing encloses a containment vessel holding a liquid to beaerosolized, an electrohydrodynamic apparatus for aerosolizing theliquid and delivering the aerosol to the exit opening, a power supplyfor providing sufficient voltage to the electrohydrodynamic apparatus toaerosolize the liquid, and a dispensing system for delivering the liquidto be aerosolized from the containment vessel to the electrohydrodynamicsystem.

The dispensing system may include a metering system for dispensing adesired amount of the liquid to the electrohydrodynamic apparatus, whichmay comprise a mechanically-actuated piston pump. The metering systemand the control circuit may cooperate to provide a dose counter or adose display, which may show the doses administered or the dosesremaining. The control circuit may include a timer that cooperates tolimit the delivery of the liquid by the metering system. The controlcircuit also may include a signal that cooperates with the timer toalert a user that a dose is due by an alarm or a visual display showingthe time when the next dose is due.

The control circuit includes a memory for storing dose information to beprovided to the metering system or recording the dose history.

The electrohydrodynamic apparatus of the device may include a chargeneutralizer for aiding in the delivery of the drug to a user's lungs.The electrohydrodynamic apparatus also may include a generally circularbase plate having upper and lower surfaces; a plurality of spray sitesarranged in a circular pattern along the perimeter of the lower surfaceof the base plate, each of the spray sites having a base end mounted tothe base plate and a tip end oriented vertically downward; a skirtextending downward from the base plate; a plurality of dischargeelectrodes each extending radially inward from the skirt in the area ofthe spray site tip ends; and a plurality of reference electrodes eachextending radially inward from the skirt downstream of and between thedischarge electrodes. A dielectric material may be enclosed within theskirt or the skirt may be comprised of a dielectric material.

The tip end of at least one spray site may be chamfered. The exterior ofat least one of the spray sites also may be coated with a low surfaceenergy coating. The electrohydrodynamic apparatus further may include amanifold extending between the dispensing system and the base ends ofthe spray sites.

In another preferred embodiment, the pulmonary aerosol delivery deviceincludes a housing sized so it can be held in a user's hand and havingan exit opening for directing the aerosol to the user's mouth. Thehousing includes a dispensing system for containing the liquid to beaerosolized and delivering it to an electrohydrodynamic apparatus; anelectrohydrodynamic apparatus for aerosolizing the liquid and deliveringthe aerosol to the exit opening; and a power supply system for providingsufficient voltage to the electrohydrodynamic apparatus to aerosolizethe liquid. The electrohydrodynamic device includes a spray site havinga sufficient electric field strength that a net electrical charge isimparted to the surface of a liquid flowing over the spray site, withthe surface charge initially balancing the surface tension of the liquidto cause the liquid to form a cone and eventually overcoming the surfacetension of the liquid in the region of the tip of the cone to generate athin jet of liquid that breaks into droplets of respirable size.

In a preferred embodiment, the method of orally administering anaerosolized liquid therapeutic agent includes the steps of storing theliquid in a containment vessel; dispensing the liquid from thecontainment vessel to an electrohydrodynamic apparatus; electricallyactuating the electrohydrodynamic apparatus to aerosolize the liquid;metering a desired amount of liquid to be dispensed from the containmentvessel to the electrohydrodynamic apparatus; and enclosing thecontainment vessel and electrohydrodynamic apparatus within a cordlesshousing of such size that it can be held in a user's one hand, thehousing including an exit opening for directing the aerosol to theuser's mouth. In the above-described method, the treating step mayinclude neutralizing the electrical charge imparted to the aerosolizedliquid and the electrical actuation step may be initiated by a user'sinhalation of breath.

In another preferred embodiment, the method for orally administering anaerosolized liquid therapeutic agent comprises the steps of storing theliquid in a containment vessel; metering a desired amount of liquid tobe dispensed from the containment vessel to the electrohydrodynamicapparatus; dispensing the liquid from the containment vessel to anelectrohydrodynamic apparatus; electrically actuating theelectrohydrodynamic apparatus to aerosolize the liquid; treating theaerosolized liquid to modify an electrical charge imparted to theaerosolized liquid by the electrohydrodynamic apparatus; and enclosingthe containment vessel and electrohydrodynamic apparatus within acordless housing of such size that it can be held in a user's one hand,the housing including an exit opening for directing the aerosol to theuser's mouth. The electrical actuation step may be initiated by a user'sinhalation of breath.

Another preferred embodiment of the pulmonary aerosol delivery devicecomprises a housing of such size that it can be held in a user's onehand, the housing having an exit opening for directing the aerosol tothe user's mouth and including therein, a dispensing system forcontaining the liquid to be aerosolized and delivering it to anapparatus for aerosolizing the liquid; an apparatus for aerosolizing theliquid and delivering the aerosol to the exit opening; and a powersupply system for providing sufficient voltage to the aerosolizingapparatus to aerosolize the liquid. The apparatus for aerosolizing theliquid comprises a plurality of spray sites each having a tip end, thespray sites cooperating with a charge source to result in anelectrohydrodynamic spray from at least one tip end, a plurality ofdischarge electrodes downstream of the tip ends, and a plurality ofreference electrodes downstream of the plurality of dischargeelectrodes.

The invention also encompasses an apparatus for aerosolizing a liquid.In one preferred embodiment, the aerosolizing apparatus comprises aplurality of spray sites each having a tip end, the spray sitescooperating with a charge source to result in an aerosolized spray fromat least one tip end, a plurality of discharge electrodes downstream ofthe tip ends, and a plurality of reference electrodes downstream of theplurality of discharge electrodes. The apparatus also may include acharge source for charging the spray sites sufficiently to result in anelectrohydrodynamic spray from at least one tip end.

The plurality of discharge electrodes and the plurality of referenceelectrodes may be oriented toward the aerosolized spray and particularlymay be oriented radially toward the aerosolized spray. Preferably, theplurality of discharge electrodes are spaced equidistant from oneanother and the plurality of reference electrodes are located in theinterstices between the discharge electrodes.

The aerosolizing apparatus also may include a dielectric materialbetween the plurality of discharge electrodes and the plurality ofreference electrodes. The reference electrodes may extend through slotsprovided in the dielectric material.

Preferably, at least one of the plurality of spray sites has asufficient electric field strength that a net electrical charge isimparted to the surface of a liquid flowing over the spray site suchthat the surface charge initially balances the surface tension of theliquid to cause the liquid to form a cone and eventually overcomes thesurface tension of the liquid in the region of the tip of the cone togenerate a thin jet of liquid that breaks into aerosolized droplets ofrespirable size. At least one of the plurality of discharge electrodesmay have a sufficient electric field strength to substantiallyneutralize a charge on the aerosolized droplets generated by the spraysite.

The tip ends of the plurality of spray sites may be oriented verticallydownward. Preferably, the plurality of spray sites are arranged in agenerally circular pattern and are spaced equidistant from one another.The tip end of at least one of the plurality of spray sites may bechamfered. Also, the exterior of at least one of the plurality of spraysites may be coated with a low surface energy coating.

Another preferred aerosolizing apparatus comprises a tubular base havinga generally circular cross-section, a plurality of spray sites eachhaving a tip end extending axially into a first end of the base, thespray sites cooperating with a charge source to result in an aerosolizedspray from at least one tip end, a plurality of discharge electrodeseach connected to the interior of the base downstream of the spraysites, and a plurality of reference electrodes each connected to theinterior of the base downstream of the plurality of dischargeelectrodes. The apparatus may further include a charge source forcharging the spray sites sufficiently to result in anelectrohydrodynamic spray from at least one tip end.

Preferably, the plurality of discharge electrodes and the plurality ofreference electrodes are oriented toward the aerosolized spray. Theplurality of discharge electrodes may be located in the area of the tipends of the plurality of spray sites.

In the above-described aerosolizing apparatus, at least one of theplurality of spray sites preferably has a sufficient electric fieldstrength that a net electrical charge is imparted to the surface of aliquid flowing over the spray site such that the surface chargeinitially balances the surface tension of the liquid to cause the liquidto form a cone and eventually overcomes the surface tension of theliquid in the region of the tip of the cone to generate a thin jet ofliquid that breaks into aerosolized droplets of respirable size. Atleast one of the plurality of discharge electrodes may have a sufficientelectric field strength to substantially neutralize a charge on theaerosolized droplets generated by the spray site.

The plurality of reference electrodes and the plurality of dischargeelectrodes may extend radially inwardly from the interior of the base.The plurality of discharge electrodes preferably are spaced equidistantfrom one another and the plurality of reference electrodes are locatedin the interstices between the discharge electrodes.

The aerosolizing apparatus also may include a dielectric material withinthe base between the discharge electrodes and the reference electrodes.Preferably, the reference electrodes extend through slots provided inthe dielectric material.

The tip ends of the plurality of spray sites provided in theaerosolizing apparatus preferably are oriented vertically downward. Theplurality of spray sites may be arranged in a predetermined pattern, andparticularly in a generally circular pattern.

In yet another preferred embodiment, the aerosolizing apparatuscomprises a generally circular base plate having upper and lowersurfaces, a plurality of spray sites arranged in a circular patternalong the perimeter of the lower surface of the base plate, each of thespray sites having a base end mounted to the base plate and a tip end,the spray sites cooperating with a charge source to result in anaerosolized spray from at least one tip end, a skirt extending downwardfrom the base plate, a plurality of discharge electrodes each extendingfrom the skirt downstream of the spray site tip ends; a plurality ofreference electrodes each extending from the skirt downstream of thedischarge electrodes, and a dielectric material between the plurality ofdischarge electrodes and the plurality of reference electrodes. Thedielectric material may be a discrete member provided within the skirtor the skirt may be comprised of a dielectric material. The aerosolizingapparatus also may include a charge source for charging the spray sitessufficiently to result in an electrohydrodynamic spray from at least onetip end.

The plurality of reference electrodes may be positioned in intersticesbetween the discharge electrodes. Preferably, the plurality of dischargeelectrodes are spaced equidistant from one another with the plurality ofreference electrodes are located in the interstices between thedischarge electrodes. The reference electrodes may extend through slotsprovided in the dielectric material.

In the above-described aerosolizing apparatus, at least one of theplurality of spray sites preferably has a sufficient electric fieldstrength that a net electrical charge is imparted to the surface of aliquid flowing over the spray site such that the surface chargeinitially balances the surface tension of the liquid to cause the liquidto form a cone and eventually overcomes the surface tension of theliquid in the region of the tip of the cone to generate a thin jet ofliquid that breaks into droplets of respirable size. At least one of theplurality of discharge electrodes may have a sufficient electric fieldstrength to substantially neutralize a charge on the aerosolizeddroplets generated by the spray site.

BRIEF DESCRIPTION OF THE DRAWINGS

These and further objects of the invention will become apparent from thefollowing detailed description.

FIG. 1 is a perspective view of a device of the present invention with atop portion of the housing removed.

FIG. 2 is an exploded view of the device of FIG. 1.

FIG. 3A is a detail view of a preferred nozzle useful in the device ofthe present invention.

FIG. 3B is a bottom view of the nozzle of FIG. 3A.

FIG. 3C is a cross-sectional view of the nozzle of FIG. 3B along lineA-A.

FIG. 4 is a state diagram showing the relationships among theoperational states of an embodiment of the device of the presentinvention.

FIG. 5 is a side elevational view of a containment vessel and meteringsystem useful in the device of the present invention.

FIG. 6 is a cross-sectional view of the containment vessel and meteringsystem of FIG. 5 along line B-B.

FIG. 7 is a cross-sectional view of the containment vessel and meteringsystem of FIG. 5 along line C-C.

DETAILED DESCRIPTION OF CERTAIN PREFERRED EMBODIMENTS

The invention described here provides a compact, convenient apparatusfor delivering an aerosolized liquid having therapeutic properties to auser's lungs. The hand-held pulmonary drug delivery device efficientlyaerosolizes a therapeutic liquid into droplets of respirable size andadministers a clinically relevant dose of a variety of therapeuticliquids to a user.

Liquids amenable to aerosolization by electrohydrodynamic sprayinggenerally are characterized by particular electrical and physicalproperties. Without limiting the scope of the invention, liquids havingthe following electrical and physical characteristics permit optimumperformance by the device and method to generate a clinically relevantdose of respirable particles within a few seconds. The surface tensionof the liquid typically is in the range of about 15-50 dynes/cm,preferably about 20-35 dynes/cm, and more preferably about 22-33dynes/cm. Liquid resistivity typically is greater than about 200ohm-meters, preferably greater than about 250 ohm-meters, and morepreferably greater than about 400 ohm-meters. The relative electricalpermittivity typically is less than about 65, preferably less than about45. Liquid viscosity typically is less than about 100 centipoise,preferably less than about 50 centipoise. Although the above combinationof characteristics allows optimum performance, it may be possible toeffectively spray liquids with one or more characteristics outside thesetypical values using the device and method of the invention. Forexample, certain nozzle configurations may allow effective spraying ofless resistive (more conductive) liquids.

Therapeutic agents dissolved in ethanol generally are good candidatesfor electrohydrodynamic spraying because the ethanol base has a lowsurface tension and is nonconductive. Ethanol also is an antimicrobialagent, which reduces the growth of microbes within the drug formulationand on the housing surfaces. Other liquids and solvents for therapeuticagents also may be delivered using the device and method of theinvention. The liquids may include drugs or solutions ormicrosuspensions of drugs in compatible solvents.

As described above, the electrohydrodynamic apparatus aerosolizes theliquid by causing the liquid to flow over a region of high electricfield strength, which imparts a net electric charge to the liquid. Inthe present invention, the region of high electric field strengthtypically is provided by a negatively charged electrode within the spraynozzle. The negative charge tends to remain on the surface of the liquidsuch that, as the liquid exits the nozzle, the repelling force of thesurface charge balances against the surface tension of the liquid,forming a Taylor cone. The electrical force exerted on the liquidsurface overcomes the surface tension at the tip of the cone, generatinga thin jet of liquid. This jet breaks into droplets of more or lessuniform size, which collectively form a cloud.

The device produces aerosolized particles of respirable size.Preferably, the droplets have a diameter of less than or equal to about6 microns, and more preferably, in the range of about 1-5 microns, fordeep lung administration. Because many formulations are intended fordeep-lung deposition, at least about 80% of the particles preferablyhave a diameter of less than or equal to about 5 microns for effectivedeep lung administration of the therapeutic agent. The aerosolizeddroplets are substantially the same size and have near zero velocity asthey exit the apparatus.

The range of volumes to be delivered is dependent on the specific drugformulation. Typical doses of pulmonary therapeutic agents are in therange of 0.1-100 μL. Ideally, the dose should be delivered to thepatient during a single inspiration, although delivery during two ormore inspirations may be acceptable under particular conditions. Toachieve this, the device generally must be capable of aerosolizing about0.1-50 μL, and particularly about 10-50 μL, of liquid in about 1.5-2.0seconds. Delivery efficiency is also a major consideration for thepulmonary delivery device so liquid deposition on the surfaces of thedevice itself should be minimal. Optimally, 70% or more of theaerosolized volume should be available to the user.

The hand pulmonary delivery device is cordless, portable, and smallenough to be held and operated with one hand. Preferably, the device iscapable of delivering multiple daily doses over a period of at least 30days without requiring a refill or other user intervention.

The pulmonary delivery device 10 of the present invention, shown inFIGS. 1 and 2, includes a housing 12 sized so that it can be held in auser's hand. The housing 12 has an exit opening 14 for directing theaerosol to the user's mouth. The housing 12 encloses a dispensing system20 for containing the liquid to be aerosolized and delivering it to anelectrohydrodynamic apparatus 30, an electrohydrodynamic apparatus 30for aerosolizing the liquid and delivering the aerosol to the exitopening 14, and a power supply 50 for providing a sufficient voltage tothe electrohydrodynamic apparatus 30 to aerosolize the liquid. Thedevice 10 may include a control circuit 60 that communicates with thedispensing system 20, the electrohydrodynamic apparatus 30, and thepower supply 50.

Dispensing System. The dispensing system 20 holds the supply of theliquid to be aerosolized and delivers a single dose of the liquid to theelectrohydrodynamic apparatus 30. The dispensing system 20 generallydelivers the liquid to a single position in the nozzle 32 of theelectrohydrodynamic apparatus 30. If the nozzle 32 has multiple spraysites 34 (shown in FIG. 3A), the nozzle 32 typically performs thefunction of distributing the liquid to the various spray sites 34,although it also would be possible for the dispensing system 20 toperform this function.

The dispensing system 20 includes a containment vessel 22 for containingand maintaining the integrity of the therapeutic liquid. The containmentvessel 22 may take the form of a holder for a drug enclosed in singledose units, a plurality of sealed chambers each holding a single dose ofthe drug, or a vial for enclosing a bulk supply of the drug to beaerosolized. Bulk dosing generally is preferred for economic reasonsexcept for liquids that lack stability in air, such as protein-basedtherapeutic agents.

The vessel 22 preferably is physically and chemically compatible withthe therapeutic liquid including both solutions and microsuspensions andis liquid- and air-tight. Vessel 22 may be treated to give itantimicrobial properties to preserve the purity of the liquid containedin the vessel 22. The material of the vessel and any antimicrobialcoating applied thereto are biocompatible.

The vessel 22 may be capable of maintaining the sterility of a sterileliquid placed therein. Preferably, vessel 22 is aseptically filled andhermetically sealed to maintain sterility of the therapeutic liquidduring its shelf life. This may be accomplished, for example, using a“form, fill, seal” process or a “blow, fill, seal” process. The vessel22 remains sealed until it is connected to the dispensing system 20prior to the first use. After the first use, seals or check valvesbetween the vessel 22 and the dispensing system 20 and unidirectionalflow of the liquid maintain the integrity of the liquid in the vessel22. In a preferred embodiment, vessel 22 is an easily collapsible thinpouch. The shape, collapsibility and outlet orifice of the pouch allowmaximum withdrawal of a drug.

When bulk dosing is used, the dispensing system 20 includes a dosemetering system 24 for withdrawing a predetermined, precise dose of theliquid from the containment vessel 22 and delivering this dose at acontrolled flow rate to the nozzle 32 of the electrohydrodynamicapparatus 30. Preferably, the dose metering system 24 is capable ofconsistently metering the desired dose to within at least about ±10%,and more preferably ±5%, of the set dose volume.

The dose metering system 24 may comprise a piezoelectric pump(including, but not limited to, the pump described in copending U.S.patent application Ser. No. 220,310 titled “Piezoelectric Micropump,”filed Dec. 23, 1998), a manually or mechanically operated piston pump,or a pressurized gas. For example, a small motor may be coupled to gearsto rotate a screw that in turn depresses the plunger of a vial such asthose customarily used for insulin.

FIGS. 5-7 show a dispensing system 100 including a containment vessel 96coupled with a manually actuated piston pump metering system 98. Thepump 98 is actuated by depressing a button 102 that protrudes throughthe housing. Depressing the button 102 compresses button spring 106against chamber housing 108, forcing the housing 108 downward. As thechamber housing 108 moves downward, liquid is forced from the chamber112 below the housing 108 through capillary tube 114 and outlet checkvalve 116. The button 102 is held until chamber housing 108 is fullylowered.

When chamber housing 108 is fully lowered and the button 102 isreleased, the now compressed chamber housing spring 118, located belowchamber housing 108, forces the chamber housing 108 upward. The vacuumformed in the chamber 112 as the housing 108 rises draws liquid into thechamber 112 from the containment vessel 96 through needle 120 andchamber check valve 122. Chamber housing 108 continues to rise until itreaches dose adjuster stop 124. The position of the dose adjuster 130relative to the piston housing 126 limits the travel of the chamberhousing 108, which controls the chamber volume (dose). The stop 124 mayinclude a threaded or other suitable adjustment 128. Flow rate may becontrolled by the spring rates of springs 106, 118. The piston 110 andcheck valves 116, 122 provide unidirectional liquid flow.

Returning to FIGS. 1 and 2, the pump or other metering system 24 may beformed from injection molded plastic or other suitable material.Preferably, this material will have antimicrobial properties or becoated with an antimicrobial coating. The material and antimicrobialcoating of the metering system 24 are biocompatible. Passages within themetering system 24 that may contact liquid are compatible with theliquid, biocompatible, and of a design and size compatible withsolutions and microsuspensions. The metering system 24 is actuated bythe control circuit 60 as described below.

The material of the metering system 24 is compatible with sterilizationtechniques. Preferably, the metering system 24 will be packaged in asterile condition to provide a sterile shelf life. As described above,after the first use, seals such as check valves 116, 122 andunidirectional liquid flow maintain the integrity of the liquid in thepassages of the metering system 24.

The metering system 24 and control circuit 60 may cooperate to provide adose counting function. The device 10 may include a dose display showingthe doses administered and the doses remaining. The dispensing system 20(and particularly the metering system 24) may cooperate with the controlcircuit 60 to limit the delivery of the liquid to predetermined times orintervals.

Electrohydrodynamic Apparatus. The electrohydrodynamic apparatus 30functions by electrically charging the liquid to be aerosolized untilthe repulsive force of the charge overcomes the force of surfacetension, causing the bulk liquid to be broken into minute droplets. Theelectrohydrodynamic apparatus 30′ provides a sufficient volumetric flowrate of liquid so that a desired amount of a therapeutic liquid may bedelivered during a user's inhalation of a single breath. This flow ratehas not been achieved before in a hand-held inhaler 10. Preferrednozzles achieve aerosolization of particles in the respirable range athigh flow using multiple spray sites in a compact configuration suitablefor use in a hand-held device, with minimal wetting losses and arcing.

In electrohydrodynamically-generated aerosols, it generally is knownthatD_(p)∝Q^(1/3)where D_(p) is the particle diameter and Q is flow rate. While spray tipgeometry, its association with other electrodes, and the formulationcharacteristics affect the effective flow rate, stable Taylor cones anda high fraction of respirable particles can be maintained only if theflow rate per spray site is about 1 μL/sec or less. The number andconfiguration of spray sites therefore determines the maximum flow rate,i.e., the maximum amount of therapeutic liquid that may be deliveredduring a user's inhalation of a single breath.

A direct correlation between the mass median diameter (MMD) of theaerosol and the flow rate also has been observed. In general, if 80% ormore of the particles are to have a diameter of 5 microns or less (asmeasured using either a Malvern Instruments Mastersizer® S or Model 2600particle size spectrum analyzer), the flow rate per site likely will beless than or equal to about 1 μL/sec, more likely less than or equal toabout 0.5 μL/sec. It is expected that delivery to a user's lungs ofparticles having this size distribution may be achieved at higher flowrates per site due to evaporation of the particles during delivery,particularly when the liquid includes a volatile solvent such asethanol.

The device 10 is capable of spraying a wide range of formulationsincluding liquid pharmaceutical solutions and suspensions. Smalladjustments in the number of spray sites, volumetric flow rate, or themagnitude of the operating voltages may be required to tailor the device10 to a specific formulation, but the basic design of the device 10 isexpected to remain constant.

As shown in FIGS. 3A, 3B, and 3C, the electrohydrodynamic apparatus 30′includes a nozzle 32′, at least one electrical reference electrode 36,and at least one neutralizing or discharge electrode 38. The nozzle 32′may include a base plate 40 and a skirt 42 extending downwardly from thebase 40. Preferably, the nozzle 32′ is located along the axis of agenerally cylindrical nozzle housing.

A dielectric material 44 may be recessed within the skirt 42, as shownin FIG. 3A. Alternatively, the skirt 42 may be comprised of a dielectricmaterial and the dielectric member 44 deleted. A flow director 37 may beprovided as shown in FIG. 3C to aid in moving air past the nozzle 32 tosweep away the aerosol as described more fully in U.S. application Ser.No. 130,873, filed Apr. 23, 1999, which is fully incorporated herein byreference. The flow director 37 may be a discrete element or integralwith the skirt 42.

The nozzle 32′ includes a plurality of spray sites 34 oriented todeliver the spray toward a user's mouth, and particularly downstreamtoward the exit opening 14 of the housing 12 of a pulmonary aerosoldelivery device 10. Preferably, the spray sites 34 are orientedvertically downward when the device is in use.

Any spray site 34 that supports formation of a Taylor cone may be used,such as capillary tubes, ball tips and conical tips. The spray sites 34may be formed integrally with the nozzle 32′, e.g., by machining orpressing. The nozzle 32′ typically performs the function of distributingthe liquid from the dispensing system 20 to the individual spray sites34.

The preferred number and arrangement of spray sites 34 provided withinthe nozzle 32′ may depend on the particular therapeutic agent or classof agents. Therapeutic agents that require high flow rates (i.e., up toabout 50 μL in about 2 seconds) require multiple spray sites 34. Whenmultiple spray sites 34 are used, the sites 34 should be positioned toreduce interaction among the spray sites 34 and between the spray sites34 and the housing 12. For spray sites 34 oriented to spray verticallydownward, circular arrangements of spray sites 34 are preferred.

In a preferred 17-spray site nozzle 32′, the spray sites 34 may beparallel capillary tubes 46 extending from base 40. The tubes 46 areintegral with a sprayer assembly having a single inlet port (not shownin the drawings). Thus, the 17-spray site nozzle 32′ has built-inmanifolding to distribute the liquid to the tubes 46, providing a nearly“instant” on and off feature when the metering system 24 is actuated anddeactuated. The tube length may vary but preferably is at least about0.003 inch.

The tubes 46 preferably are arranged in a circular pattern and spaced anequal distance from one another. The diameter of the circle is selectedto be large enough to minimize the tendency to form a single largeTaylor cone among the spray sites 34. For example, the circle may have adiameter of approximately 0.4-0.6 inches in a nozzle 32′ intended foruse in a hand-held device 10. The tubes 46 preferably are positionedclose to the edge of the base 40. This reduces both interactions amongthe tube tips 48 and electrostatic shielding of the tips 48 by theportion of the base plate 40 that extends radially beyond the circle ofthe tips 48, which allows spraying of liquids with greaterconductivities at a smaller potential than if the tips 48 were shielded.The preferred arrangement and position of spray sites 34 may vary fornozzles 32′ with different types or numbers of spray sites 34.

Droplets having a neutral charge are preferred for pulmonary delivery.The electrohydrodynamic apparatus 30 therefore includes a chargeneutralizer, in the form of a neutralizing or discharge electrode 38.The discharge electrode 38 provides a stream of ions having an oppositepolarity from those in the aerosolized droplet cloud59. The chargeddroplets engage the oppositely charged ions to form droplets having aneutral, or at least less polar, charge. Preferably, at least one of theplurality of discharge electrodes has a sufficient electric fieldstrength to substantially neutralize a charge on the aerosolizeddroplets generated by a spray site. A dielectric material may be placedbetween the spray sites 34 and the discharge electrode 38 to modify theelectric field and/or reduce the current draw of the electrohydrodynamicapparatus 30.

Discharge electrodes 38 aimed toward the sprayer axis may be positionedaround the nozzle 32′ downstream of the tip ends, preferably with thedischarge electrodes 38 oriented radially inwardly and spacedequidistant from one another in the area of the tube tips 48. The numberand position of neutralizing electrodes 38 may vary with the number andconfiguration of spray sites 34. Eight discharge electrodes 38 in theposition illustrated have produced satisfactory results in the 17-spraysite nozzle 32′.

A plurality of reference electrodes 36 is arranged downstream of thedischarge electrodes 38, best shown in FIG. 3C, with the referenceelectrodes 36 aimed toward the axis. In a preferred nozzle 32′, thereference electrodes 36 are oriented radially inwardly. The referenceelectrodes 36 may extend through slots in the dielectric material 44below the discharge electrodes 38. Preferably, the number of referenceelectrodes 36 is equal to that of the discharge electrodes 38 such thatthe reference electrodes 36 may be positioned between and downstream ofthe discharge electrodes 38, best shown in FIG. 3B.

The reference electrodes 36 are maintained at a potential between thatof the spray tip ends 48 and the discharge potential, which may but neednot be true ground. It may be possible to obtain satisfactory resultsusing reference electrodes that define a continuous ring rather than aplurality of individual reference electrodes 36. However, use of aplurality of reference electrodes 36 rather than a continuous ring andthe interstitial positioning of the reference electrodes 36, providessuperior resistance to wetting. The interstitial reference electrodes 36also reduce arcing by virtually eliminating a liquid conductive pathbetween the nozzle tips 48 and the reference electrodes 36. A currentlimiting resistor may be used to further control arcing.

The spray sites cooperate with a charge source sufficient to result inan electrohydrodynamic spray from at least one tip end. Preferably, eachspray site 34 in the 17-spray site nozzle 32′ produces a Taylor cone andforms an aerosol jet. The spray angle is not strictly downward butincludes a radial component as a result of electrostatic interactionamong the tube tips 48 which causes the sprays to repel one another. Theradial component of the spray angle is not great enough to result inunacceptable losses from wetting of the housing 12. Wetting may bereduced by the use of a dielectric or some other material to modify theelectric field. As described above, the skirt 42 may also be designed tocontrol airflow streaming past the nozzle to control deposition ofaerosol droplets and to stabilize the Taylor cone. Preferably, the edgesof the tubes 46 are chamfered to improve Taylor cone formation.

A 17-spray site nozzle 32′ with the above-described dischargeconfiguration is capable of aerosolizing particles in the respirablerange at a flow rate of up to about 20 μL/sec as measured with either aMalvern Instruments Mastersizer® S or Model 2600 particle size spectrumanalyzer. The nozzle 32′ is capable of spraying an aerosol of respirableparticle size with a tight distribution at lower flow rates (7-10μL/sec). At higher flow rates, a distinct knee may be observed at thehigh end of the distribution.

The 17-spray site nozzle 32′ was tested in a delivery system consistingof a mouthpiece and a source of continuous controlled air flow. A 1%Triamcinolone formulation (in 80% ethanol/20% polyethylene glycol 300)was aerosolized at a flow rate of 15 μL/sec, with as particle sizedistribution of 4.9 microns MMD as measured by a Malvern InstrumentsMastersizer® S particle size spectrum analyzer. At 10 μL/s, thedistribution was monodispersed with a MMD of 3.7 microns. At 7 μL/s, theMMD was less than 3 microns, with 80% or more of the particles having adiameter less than 5 microns. Similar results were obtained with a 1%Albuterol free base formulation (in 80% ethanol/20% polyethylene glycol300). Measurements with an Anderson cascade impactor confirmed all ofthe results achieved with the Mastersizer® analyzer.

Wicking losses, which may occur even when the electric field is off,must be controlled to allow both sustained operation of the device anddelivery of the expected dose of the therapeutic liquid to a user. Ifuncontrolled, wicking may result in submersion of the nozzle andcessation of spray activity. Wicking losses are thought to result fromthe low surface tensions of the liquid formulations (as low as about 15dynes/cm). To control wicking, the outer diameter of the spray sites 34or other surfaces of interest may be coated with a low surface energycoating. Applying the critical surface energy concept pioneered byZisman, a coating having a solid surface energy well below 15 dynes/cmshould be selected. Fluorocarbon coatings having surface energies lowerthan that of Teflon (about 18 dynes/cm) are believed to be suitable forsuch use. When the tubes 46 of the 17-spray site nozzle 32′ are coatedwith a low surface energy coating, the nozzle 32′ is capable of sprayingover 3,500 microliters of liquid with minimal accumulation at the base40 of the tubes 46.

The conducting (electrode) components 34, 36, 38, 40 of the nozzle 32′may be fabricated from 303 or 316 stainless steel. Other suitableconductors also may be used as long as the material is compatible withthe liquid to be sprayed, is resistant to corrosion, and does notdeteriorate during the expected life of the device. The nonconductingcomponents may be formed from machined Delrin, Lexan, or other suitablematerial.

Power Supply System. Electrospray nozzles 32 rely on high voltage tocharge the formulation as it exits the spray site 34. The power supplysystem 50 is capable of providing a voltage capable of actuating theelectrohydrodynamic apparatus 30 to produce an aerosol having desiredcharacteristics with a minimum of arcing. Voltages in the range of about2,600-6,000 V or more at very low amperages (less than about 100microamperes, and preferably less than about 50 microamperes) generallyappear to yield satisfactory results, although voltages outside thisrange may be suitable depending on the size of the device 10 and thetype of electrohydrodynamic spray nozzle 32′ used. The minimum voltagegenerally increases, for example, as the number of spray sites 34increases. A nozzle 32 with the simplest geometry (i.e., four electrodes38 and a single spray site 34) generally requires a minimum voltage ofabout 2,600 V. Typical voltages for nozzles 32′ used in the presentdevice 10 are in the range of about 4,000-5,000 V. Voltages above about6,000 V generally are difficult to achieve in a hand-held device usingconventional power supplies, but higher voltages (in the range of about2,600-20,000 V) may be usable with power supply improvements.

The power supply 50 includes a high voltage DC to DC converter,preferably a transformer based switching converter. The DC to DCconverter is connected to a battery 54, which may be included in thepower supply 50. Alternatively, the battery 54 may be incorporated intothe containment vessel 22 so that the supply of therapeutic liquid andthe battery 54 may be replaced simultaneously.

Lithium batteries are preferred because of their energy density tovolume ratio, their long shelf life and their voltage stability overtheir operating life. Other batteries such as alkaline batteries andrechargeable nickel metal hydride batteries (e.g., NiCad batteries) alsomay be used. The high voltage power supply 50 preferably has dualoutputs with one output at positive DC voltage and the second output atnegative DC voltage. The supply 50 also has a reference output,nominally at ground potential, that is common to both the positive andnegative outputs. The anticipated output voltage range is ±5000 VDC,measured with respect to the reference output. Each of the dual outputspreferably has the same tolerance and operates to within about 2% of thenominal output voltage. The maximum allowable ripple for each of thedual outputs preferably is about 1%, measured with respect to thereference output.

The power supply 50 preferably can accept an input voltage over therange of about 6-9 VDC and generate a maximum output current for each ofthe dual outputs of about 100 microamperes. The supply 50 should be ableto supply this maximum output current on both outputs simultaneously andcontinuously. The power supply 50 should not be damaged in any way ifthe outputs (one or both) are shorted to ground or shorted together fora duration of less than one minute and should resume normal operation ifthe short on the output is removed.

Practical limitations are imposed on the physical size of both the highvoltage power converter and the battery 54 in a cordless hand-held unit10. While commercially available DC-to-DC converters readily can acceptinput voltages of 12 or 24 VDC and generate outputs of 10 kV and higher,these converters are large and would be nearly impossible to packageinto a hand-held pulmonary delivery device. The voltage output ofsmaller converters often is limited to 3-6 kV. The battery size limitsthe energy available to the high voltage converter. To maintain thedesired operating life of at least thirty days with multiple doses perday, operation of the nozzle 32′ requires no more than about 1.0 wattsand preferably no more than about 0.5 watts.

For the device 10 of the present invention, the target upper limit onthe magnitude of the operating voltages for the nozzle 32′ is 5 kV.Because the package size preferably is as small as is reasonablypossible, the maximum physical envelope of the high voltage powerconverter preferably is about 2.0″×0.7″×0.6″ (50.8 mm×17.8 mm×15.24 mm)and the maximum weight of the high voltage power converter preferably isabout 30 grams (1 ounce).

The power supply 50 preferably is fully encapsulated using glass-filledepoxy or an equivalent conformal coating having the dielectric strengthto allow tight packaging of the high voltage conversion circuitry into asmall volume. Any wires emanating from the power supply modules 50 willhave sufficient insulation to meet the requirements of EN60601 andUL2601 standards.

Control Circuit. The device 10 includes a control circuit 60communicating with the dispensing system 20, the electrohydrodynamicapparatus 30, and the power supply system 50. The power supply system 50may be integrated into the control circuit 60. Preferably, a singleintegrated circuit 60 such as a programmable logic device (PLD) controlsall the functions of the device 10, which may include metering control,actuating devices, high voltage control, power save feature, statusindicators, user inputs, dose counting and breath sensing. It isexpected that the integrated circuit 60 can control all desiredfunctions without software, but the device 10 also may performeffectively with a control circuit 60 including software.

The control circuit 60 includes an actuation device for initiating theflow of aerosolized liquid. The actuation device may include a sensor(not shown in the drawings) for detecting a user's inhalation of breaththat cooperates with the electrohydrodynamic apparatus 30 to initiatethe aerosol flow. For example, the breath sensor may be a flapperswitch, a pressure transducer, or a piezoelectric or other air motion orair velocity detector. Alternatively, the actuation device may comprisea manual actuator 64 on the exterior of the housing 12.

In the manually-actuated device 10 (i.e., a device without a breathsensor), the control circuit 60 includes an On/Off button 62 and aDosing button 64 or equivalent devices on the exterior of the housing12. These actuators 62, 64 preferably are actuated easily by users withlimited abilities.

The On/Off button 62 initially causes the control circuit 60 to actuatethe high voltage supply 50, a shut-down timer and a self-primingfeature. Actuation of the On/Off button 62 may be indicated byillumination of a power status indicator. The Dosing button 64 actuatesthe metering 24 or dispensing 22 control. Manual operation of the device10 therefore requires two inputs from the user (or person assisting theuser). The On/Off and Dosing buttons 62, 64 must be pressed in sequencefor the dose to be delivered. If the buttons 62, 64 are pressed in thewrong order the device 10 will turn on but no drug will be delivered.Multiple actuations of either button 62, 64 within a specified intervalare treated as a single actuation.

The operation of the device 10 may be accomplished by a series of timersand clocks that are inputs for a state machine. The device 10 steps from“state” to “state” as a result of clocked inputs, with the outputsdetermined by the operational “state” then in effect. The state machinemay be implemented in a PLD control circuit 60 such that control signalsto the various subsystems originate from the PLD 60.

In one potential control paradigm for a manually-actuated device 10, thestate machine consists of five states as shown in FIG. 4. The Off orPower Save state 66 is the baseline state for the control system 60 whenthe device 10 is not functioning. In this state 66, the high voltagesupply 50 is turned off and the current draw from the battery 54 isminimal.

The Warm-Up state 68 is entered when the user presses the On/Off button62 and the drug vessel 22 is not empty. A status LED, visible on theexterior of the housing 12, illuminates green. The high voltage supply50 and the shut down timer are turned on in this state 68. Self-priming,which causes the liquid to fill the residual nozzle volume and bedelivered to the spray sites 34 so aerosolization can begin immediatelyupon actuation of the Dosing button 64 or a breath sensor, also isturned on in the Warm-Up state 68. The shut down timer ensures that ifthe Dosing button 64 is not pressed within a specified time afterentering the Warm-Up state 68, for example, about 12 seconds, the device10 will return to the Off state 66. A purge cycle may be carried outbefore the device 10 returns to the Off state 66 to expel from thedevice 10 the unused liquid supplied to the electrohydrodynamicapparatus 30 during self-priming.

Actuation of the Dosing button 64 while the device 10 is in the Warm-Upstate 68 (e.g., within about twelve seconds of pressing the On/Offbutton 62), causes the control system 60 to enter the Breathe state 70.Actuation of the Dosing button 64 is associated with a flashing greenbreath prompt indicator followed by the solid green indicator displayduring the breath hold period. The device 10 will not respond toactuation of the Dosing button 64 until the previous dosing cycle iscompleted. The allowed interval between doses may be preset to allow orprohibit administration of sequential doses.

In the Breathe state 70, the metering control system 24 is activated forapproximately two seconds to deliver drug to the nozzle 32. This causesthe nozzle 32 to begin aerosolizing the drug immediately. After aboutfour seconds, the control system 60 exits this state 70 and enters theHold state 72. Once in the Hold state 72, the device 10 will wait aboutfour additional seconds to allow any remaining material on the nozzle 32to be aerosolized before entering the Finish state 74. (If a breathsensor is present, the device enters the Finish state 74 if there is nosignal from this sensor after being in the Breathe state 72 for aboutone second.)

Once the control system 60 enters the Finish state 74, the high voltagesupply 50 is turned off. If the device 10 includes a purge cycle foremptying unused or residual liquid from the electrohydrodynamicapparatus 30, this cycle may be actuated in the Finish state 74. Thecontrol system 60 stays in the Finish state 74 until the run-timecounter reaches about twenty seconds. Once the run-time counter timesout, all status indicators are turned off and the control system 60returns to the Off state 66.

As described above, the control circuit 60 may communicate with andcontrol the metering system 24 by PLD output in response to actuation ofthe Dosing button 64. The control circuit 60 may have a memory forstoring dose information, which may then be provided to the meteringsystem 24. Drug dosing within the hand-held device 10 can be implementedwith a variety of mechanisms such as those described above.

For a motor-driven metering system, the PLD activates the motor forabout the first two seconds of the Breathe state in the dosing cycle.Dose volume is determined by the gearing of the motor and the voltagethat is applied to the motor. Both are held constant in the currentdesign and yield, for example, a 20 μl dose. For a piezoelectricmicropump, the PLD output forms a pulse train that is applied to thepiezoelectric valves that make up the pump. The timing within the pulsetrain provides the proper valve actuation for pumping.

The high voltage power supply 50 may be actuated by a simple on/offfunction controlled by the PLD 60. The magnitude of the high voltageoutput is determined by the design of the power supply 50 and cannot bealtered by the user or clinician. In a preferred embodiment, the highvoltage supply 50 becomes active upon actuation of the On/Off button 62.During a normal operating cycle in which the Dosing button 64 isdepressed and drug is delivered, the high voltage supply 50 is activefor about twenty seconds. If the Dosing button 64 is not depressed, thehigh voltage power supply 50 is deactivated after about twelve seconds.

The control circuit 60 preferably will include indicators to display thedevice status, which may, for example, comprise LED indicators. Apreferred combination and arrangement of LEDs is described. Othercombinations and arrangements of indicators (including indicators madefrom components other than LEDs) also may be used to accomplish the sameobjectives.

A preferred embodiment includes a two-LED combination (not shown in thedrawings) in which one LED is a power status indicator and the other isa breath prompt signal. The power status LED preferably indicates asingle color, preferably green. This indicator follows the sameoperating cycle as the high voltage power supply 50: the indicator isilluminated when the On/Off button 62 is actuated and remainsilluminated while the high voltage power supply 50 is active.Illumination of the power status LED indicates that the device 10 isready for normal operation.

The breath prompt LED preferably indicates each of three operationalstates for the device 10: Breathe, Hold Breath, and Unit Empty. This maybe accomplished, for example, using an LED that is capable of flashinggreen, solid green, and solid yellow indications. The flashing green isdisplayed when the device 10 enters in the Breathe state 70 andcontinues for about four seconds. The flashing green alerts the userthat the drug is being delivered and that the user should breathe indeeply while the flashing green is displayed.

The solid green indication appears after the flashing green indicationis complete and lasts about four seconds. The solid green alerts usersto hold their breath for a short time after inhaling of the aerosolizedliquid to promote retention of the aerosol in the lungs for a longenough time for effective liquid absorption.

The solid yellow indicator is illuminated any time the device 10 isactivated (e.g., by pressing the Dosing button 64) after the last doseis delivered. The solid yellow indicates to the user that the vessel 22is empty and maintenance is required. Preferably, dose status iscontrolled by a signal from a dose counter. Dose counting may beimplemented using the PLD 60 or other means such as a mass or volumesensor in the vessel 22. When the PLD 60 is used, the dose count isincremented upon completion of a dosing cycle. When the dose countreaches a preset limit, the device 10 indicates an empty vessel 22 bydisplaying the solid yellow LED display and will no longer function.After the device is serviced, the dose counter may be reset and normaloperation cycles may be resumed.

The control circuit 60 may have a memory for recording dose informationand/or dose history. The control circuit 60 may communicate withmetering system 24, for example, by sending dose information stored inits memory to the metering system 24. The metering system 24 in turn maysend dose history information to the control circuit 60 for storage inits memory.

The device 10 preferably includes a breath sensor to determine if properinhalation was occurring during spraying. The PLD 60 may monitor thestatus of the breath sensor. If no breath is sensed one second after theDosing button 62 is actuated, the PLD 60 will signal the high voltagepower supply 50 and the metering system 24 to shut down and drugdelivery will cease.

In a particularly preferred embodiment, the device 10 is actuated by auser's breath rather than a Dosing button 64 to optimize intake of theaerosol by a user. In this preferred operational mode, the device 10primes itself upon actuation of the On/Off button 62 by moving liquid tothe spray site tips 48 so that drug delivery can begin immediately uponactuation of the Dosing button 64. The flow of the aerosol is actuatedby a user's inhalation of breath, eliminating the need for the user tocoordinate his or her breathing with actuation of the device 10. Toaccomplish this, the actuation device comprises a breath sensor thatcooperates with the electrohydrodynamic apparatus 30 to initiate theaerosol flow. The sensor also may detect a multiple breaths by a userand cooperate with the control circuit 60 to display this on a multiplebreath indicator. If desired, a manual actuator such as Dosing button 64may be provided in addition to the breath sensor.

A lockout (not shown in the drawings) cooperating with a keypad, smartring, magnetic ring, or the like may be incorporated into the controlcircuit 60 to prevent use by an unauthorized user. The device 10 alsomay include a position sensor that prevents operation of the device 10unless the electrohydrodynamic apparatus 30 is in a predetermined (e.g.,vertical) orientation.

The control circuit 60 may include a timer that cooperates with thedispensing system 20 to limit the delivery of the liquid topredetermined times or time intervals. The timer also may provide asignal to alert the user, by a display or alarm, that a dose is due.

Housing. The housing 12 preferably is constructed from a durable, easilycleanable, nonconductive, biocompatible, inexpensive material compatiblewith the liquid to be aerosolized, such as polyethylene orpolypropylene, although other suitable materials also may be used. Thematerial may be treated so that it has antimicrobial properties orprovided with a biocompatible antimicrobial coating to assist incontrolling the growth of microorganisms in and on the housing.

Typically, the housing 12 has a generally cylindrical or oblong shapethat allows the electrohydrodynamic apparatus 30 to be in asubstantially vertical position during use, but other housing shapesalso may be used. The housing 12 preferably is streamlined so it may bestored conveniently in a shirt pocket, purse, or other small space.

The housing 12 defines an exit opening 14, generally positioned on alower side wall. The exit opening 14 may include a mouthpiece 16 orcollar extending from the housing 12 to assist in directing theaerosolized liquid to the user's mouth. The mouthpiece 16 may be formedintegrally with the housing 12 or provided as a separate piece thatslides or pivots into position when needed.

The housing 12 is molded or otherwise shaped so a user easily may graspthe housing 12 and position it so that the exit opening 14 is directedtoward the user's mouth. Preferably, the housing 12 has rounded edges soa user may grasp it comfortably. Ridges may be provided on the housing12 to guide the placement of a user's fingers.

The device 10, including the housing 12 and the mouthpiece 16, musttransport the maximum amount of aerosol droplets to the user. Losses ofaerosol droplets within the housing 12 will result in delivery of alower than expected dose of the therapeutic agent to the user. Theelectrohydrodynamic apparatus 30 should be positioned within the housing12 to reduce wetting losses. With the 17-spray site nozzle 32′,positions away from the back wall of the elbow between the housing 12and the mouthpiece 16 are preferred. The 17-spray site nozzle 32′achieved transport efficiencies in the range of about 76-93 percent withan average transport efficiency of about 83 percent.

In addition to wicking losses, substantial losses may result fromdroplet deposition on the mouthpiece walls. In the present arrangement,the nozzle 32′ sprays vertically downwards and the spray must be turnedthrough an angle between 45 and 90 degrees in the mouthpiece 16 to reachthe user. Droplet deposition on mouthpiece walls as the spray turnsthrough this angle tends to result from the complex flow pattern in thebend that carries droplets towards the walls (with large dropletsimpacting the wall because of their inertia and small droplets diffusingto the wall by fluid turbulence) and turbulence produced in the flow,especially near the spray sites 34, which increases droplet diffusion tothe wall.

Losses from droplet deposition on the mouthpiece walls may be controlledby careful design of the mouthpiece shape and airflow dynamics throughthe mouthpiece 16. The interior of the housing 12 should be shaped toallow natural convection currents to aid in moving the aerosol cloud outof the housing 12. An air inlet (not shown in the drawings) may beprovided in the housing 12 in the area of the spray sites 34 to promotedischarge of the aerosolized particles. The inlet to the mouthpiece 16should be sized to assist in moving the spray around the bend and towardthe exit opening 14.

Substantial losses from droplet deposition on or near the electrodesalso may occur. These losses may be controlled by nozzle placement andgeometry. The nozzles described above result in an acceptable level oflosses at or near the electrodes.

The pulmonary delivery device 10 of the present invention may be eitherdisposable or reusable. A disposable unit 10 may have a battery 54 andcontainment vessel 22 filled with the applicable therapeutic agentsealed within housing 12. The disposable unit 10 could provide, forexample, a 30-day supply of a therapeutic agent, depending on suchfactors as the volume of therapeutic agent and its stability. Thedisposable unit 10 may include a dose counter with an indicator tosignal that all doses have been expended.

A reusable unit 10 may be provided with an initial supply of atherapeutic agent within the containment vessel 22 and a battery 54. Thehousing 12 may comprise at least two interlocking mating segments sothat it may be disassembled to refill the containment vessel 22 orreplace the battery 54. The battery 54 may be incorporated into thevessel 22 for more convenient refills.

The reusable unit 10 also may include enhancements such as electronicfeatures. These features may include, for example, dose reminder, dosecounter and dose indicator. The unit 10 also may include a lockoutcooperating with a timer to prevent overdoses or a lockout to preventuse by an unauthorized person.

Methods of Aerosol Administration. The invention also includes a methodfor oral administration of an aerosolized liquid therapeutic agent,which includes the steps of storing the liquid in a containment vessel22, dispensing the liquid from the containment vessel 22 to anelectrohydrodynamic apparatus 30, and electrically actuating theelectrohydrodynamic apparatus 30 to aerosolize the liquid. Theelectrical actuation step may be initiated by a user's inhalation ofbreath.

The method also may include the steps of metering a desired amount ofliquid to be dispensed from the containment vessel 22 to theelectrohydrodynamic apparatus 30 and enclosing the containment vessel 22and electrohydrodynamic apparatus 30 within a cordless housing 12 thatcan be held in a user's hand, the housing 12 including an exit opening14 for directing the aerosol to the user's mouth. The method of thepresent invention further may include the step of neutralizing theelectrical charge imparted to the aerosolized liquid by theelectrohydrodynamic apparatus 30.

The preferred embodiment of this invention can be achieved by manytechniques and methods known to persons who are skilled in this field.To those skilled and knowledgeable in the arts to which the presentinvention pertains, many widely differing embodiments will be suggestedby the foregoing without departing from the intent and scope of thepresent invention. The descriptions and disclosures herein are intendedsolely for purposes of illustration and should not be construed aslimiting the scope of the present invention which is described by thefollowing claims.

1. an Apparatus for aerosolizing a liquid, comprising: a base; aplurality of spray sites each having a base end connected to the baseand a tip end, an aerosolized spray being from at least one tip end whena liquid is caused to flow over the spray sites and the plurality ofspray sites is placed in electrical communication with a charge source;wherein the plurality of spray tip sites are spaced-apart from oneanother and arranged in a generally circular pattern; at least onedischarge electrode connected to the base and spaced further from thebase than the tip ends; and at least one reference electrode connectedto the base and spaced further from the base than the at least onedischarge electrode.